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Öğe Development of tripeptide-cyclotriphosphazene derivatives: In vitro cytotoxicity, genotoxicity studies and molecular docking analysis within ovarian and prostate cancer cell line receptors(Pergamon-Elsevier Science Ltd, 2024) Kaplan, Alpaslan; Caliskan, Eray; Capan, Irfan; Tekin, Suat; Hassan, Mohammad N.; Qaoud, Mohammed T.; Koran, KenanPeptide-phosphazene compounds are important compounds of growing interest in biomedical research and have potential therapeutic effects. The tripeptide-cyclotriphosphazenes conjugates were synthesized and analyzed for their molecular docking analysis, visualizing their binding profiles within various cancer cell line receptors and tested in vitro cytotoxic and genotoxic properties. Determining in vitro cytotoxic studies of obtained compounds displayed cytotoxic effect against two selected human cancer cell lines, including ovarian (A2780) and prostate (PC-3), cancer cells. The compound DTAP demonstrated significantly higher efficacy at 100 mu M in the PC-3 cancer cell line compared to the reference drug docetaxel at 50 mu M. Among the tripeptide-phosphazene conjugtates, DTGG demonstrates the most promising anticancer activity with a logIC50 of 1.23 mu M, forming five hydrogen bonds and a favorable salt bridge interaction, along with several hydrophobic interactions, thereby stabilizing its binding within the human ovarian tumor domain based on molecular docking analysis. The derivative DTGP emerges as the most potent among the DTG derivatives, achieving a Delta G model value of -108 kcal/ mol, primarily due to a lc-cationic interaction with the LYS204 amino acid in chain C, which significantly enhances its binding affinity. Additionally, DNA damage studies on human ovarian and prostate cancer cell lines determined that cell death due to DNA damage was the basis of the decrease in cell viability. These results support the evaluation of the compounds as potential drug candidates.Öğe The first peptide derivatives of dioxybiphenyl-bridged spiro cyclotriphosphazenes: In vitro cytotoxicity activities and DNA damage studies(Academic Press Inc Elsevier Science, 2023) Koran, Kenan; Caliskan, Eray; Ozturk, Dilara Altay; Capan, Irfan; Tekin, Suat; Sandal, Suleyman; Gorgulu, Ahmet OrhanIn this study, we aimed to synthesize new peptide-substituted cyclotriphosphazenes from a series of tyrosine -based peptides and dioxyphenyl-substituted spirocyclotriphosphazenes, and to evaluate their in vitro cytotox-icity and genotoxicity activities. Genotoxicity studies were conducted to understand whether the cytotoxic compounds cause cell death through DNA damage. The structures of the novel series of phosphazenes were characterized by FT-IR, elemental analysis, MS, 1D (31P, 1H, and 13C-APT NMR), and 2D (HETCOR) NMR spectroscopic techniques. In vitro cytotoxic activities were carried out against human breast (MCF-7), ovarian (A2780), prostate (PC-3), colon (Caco-2) cancer cell lines and human normal epithelial cell line (MCF-10A) at different concentrations by using an MTT assay. The compounds showed considerable reductions in cell viability against all human cancer cell lines. Especially, the compounds exhibited notable effects in A2780 cell lines (p < 0.05). The IC50 values of the compounds in the A2780 cell line were calculated to be 1.914 mu M for TG, 20.21 mu M for TV, 20.45 mu M for TA, 4.643 mu M for TP, 5.615 mu M for BTG, 1.047 mu M for BTV, 27.02 mu M for BTA, 0.7734 mu M for BTP, 21.5 mu M for DTG, 1.65 mu M for DTV, 2.89 mu M for DTA and 4.599 mu M for DTP. DNA damage studies of the compounds were conducted by the comet assay method using tail length, tail density, olive tail moment, head length, and head density parameters, and the results showed that the cell death occurred through DNA damage mechanism. In a nutshell, these compounds show promising cytotoxic effects and can be considered powerful candidate molecules for pharmaceutical applications.Öğe Phosphazene Tripeptide Conjugates: Design, Synthesis, In Vitro Cytotoxicity and Genotoxicity, Molecular Interactions in Binding Pockets on Human Breast and Colon Cancer Cell Lines(Wiley-V C H Verlag Gmbh, 2025) Caliskan, Eray; Yuksel, Furkan; Capan, Irfan; Tekin, Suat; Bouzidi, Reda; Qaoud, Mohammed T.; Biryan, FatihThe biological activity of both cyclophosphazenes and peptides makes these compounds important for new studies in medicinal chemistry. For this purpose, five different phosphazene-peptide conjugates synthesized from dichlorocyclotriphosphazene and tyrosine-containing tripeptides. The synthesized compounds were evaluated for their in vitro cytotoxic activities against human breast (MCF-7) and colon (Caco-2) cancer cell lines using MTT assay. The derivatives induced cell death through DNA damage, with notable effects in Caco-2 cell lines. Specifically, DTVV, DTVG, and DTVA were cytotoxic at 50 and 100 mu M, while DTVP and DTVM were effective at 25, 50, and 100 mu M. DTVM outperformed Tamoxifen at 50 mu M in the MCF-7 cell line. DNA damage studies of the compounds were performed using the comet assay method, evaluating tail length, tail density, olive tail moment, head length, and head density parameters. The findings indicated that cell death occurred via a DNA damage mechanism. The molecular intricacies of DTVA, DTVG, DTVM, DTVP and DTVV within the VEGFR2 kinase domain (3VHE) and Cyclophilin_CeCYP16-Like Domain (2HQ6) binding pockets and various interactions, docking scores and potential activities of these derivatives were investigated. The differences in docking scores and interaction profiles highlight the potential efficacy and specificity of these compounds in targeting breast and colon cancer cells. These findings highlight the potential of phosphazene-peptide derivatives as therapeutic agents in cancer treatment.Öğe Synthesis, docking studies, in vitro cytotoxicity evaluation and DNA damage mechanism of new tyrosine-based tripeptides(Wiley, 2023) Caliskan, Eray; Kaplan, Alpaslan; Sekerci, Guldeniz; Capan, Irfan; Tekin, Suat; Erkan, Sultan; Koran, KenanPeptides are one of the leading groups of compounds that have been the subject of a great deal of biological research and still continue to attract researchers' attention. In this study, a series of tripeptides based on tyrosine amino acids were synthesized by the triazine method. The cytotoxicity properties of all compounds against human cancer cell lines (MCF-7), ovarian (A2780), prostate (PC-3), and colon cancer cell lines (Caco-2) were determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay method, and % cell viability and logIC50 values of the compounds were calculated. Significant decreases in cell viability were observed in all cells (p < 0.05). The comet assay method was used to understand that the compounds that showed a significant decrease in cell viability had this effect through DNA damage. Most of the compounds exhibited cytotoxicity by DNA damage mechanism. Besides, their interactions between investigated molecule groups with PDB ID: 3VHE, 3C0R, 2ZCL, and 2HQ6 target proteins corresponding to cancer cell lines, respectively, were investigated by docking studies. Finally, molecules with high biological activity against biological receptors were determined by ADME analysis.Öğe Tripeptide linked dispiro cyclotriphosphazene conjugates: Synthesis, molecular docking analysis of compounds binding within cancer cell line receptors and in vitro cytotoxic and genotoxic activities(Academic Press Inc Elsevier Science, 2024) Caliskan, Eray; Capan, Irfan; Tekin, Suat; Qaoud, Mohammed T.; Biryan, Fatih; Koran, Kenan; Sandal, SuleymanThe novel dioxybiphenyl bridged-cyclotriphosphazenes (DPP) bearing tripeptide were synthesized and investigated for their molecular docking analysis, visualizing their binding profiles within various cancer cell line receptors and in vitro cytotoxic and genotoxic properties. The dipeptide compound (Tyr- Phe) was treated with various amino acids to obtain the tripeptide compounds (Tyr- Phe- Gly, Tyr- Phe- Ala, Tyr- Phe- Val, Tyr- Phe- Phe, and Tyr- Phe- Leu). These synthesized tripeptides were subsequently treated with DPP to obtain novel phosphazene compounds bearing tripeptide structures. As a result, the synthesis of target molecules with phosphazene compound in the center and biphenyl and tripeptide groups in the side arms was obtained for the first time in this study. Examining the cytotoxic studies in vitro of our newly synthesized compounds demonstrated the anticancer properties against four selected human cancer cell lines, including breast (MCF-7), ovarian (A2780), prostate (PC-3), and colon (Caco-2) cancer cells. The Comet Assay analysis determined that the cell death mechanism of most of the compounds with cytotoxic activity stemmed from the DNA damage mechanism. Among the compounds, the DPP-Tyr- Phe- Phe compound seems to have the best anticancer activity against the subjected cell lines (Except for A2780) with IC 50 values equal to 20.18, 72.14, 12.21, and 5.17 mu M against breast, ovarian, prostate, and colon cancer cell lines, respectively. For this reason, the molecular docking analysis was conducted for the DTPP compound to visualize its binding geometry and profile within the target enzyme 's binding site associated with the specific cancer cell line. The analysis revealed that the DTPP derivative exhibited an optimal binding conformation and characteristics within the target enzyme 's binding site, aligning well with the experimental data. Based on the data, these compounds are believed to be strong candidate molecules for both pharmaceutical and clinical applications.
